Morbidity and mortality due to meningococcal disease remain high despite advances in antibiotic therapy and in supportive care of septic patients. The manifestations of disseminated infection with Neisseria meningitidis develop rapidly and are often far more devastating than are those associated with bacteremia due to other gram-negative organisms. Studies implicate the high grade bacteremia and the propensity of the organism to shed large amounts of endotoxin-containing membrane vesicles as critical factors underlying the fulminant nature of serious meningococcal disease. Infection with N. meningitidis serogroup B (NMB) poses a special threat in this context, as there is no effective human vaccine against NMB. Reasoning that specific aspects of initial intravascular infection by NMB mediate the exaggerated clinical manifestations and fulminant disease, we have designed an integrated program to examine fundamental aspect of the early interactions of NMB with components of the hot innate immune system. Based on clinical and in vitro observations, we have formulated the hypothesis that the lipooligosaccharide (LOS) of meningococcal endotoxin, either as membrane vesicles or intact bacteria, elicits quantitatively and/or qualitatively different responses that does purified LOS or endotoxin from other gram-negative organisms. To test this hypothesis, we have constructed a program to define structural aspects of NMB LOS and mechanisms for its generation and release, to characterize factors mediating and modulating the mobilization of endotoxin to host targets, and to characterize the responses of phagocytes and vascular endothelial cells to endotoxin. One of the special strengths of the proposed studies is our ability to perform precise chemical analyses of species of endotoxin created by specific mutations or generated as part of the target cell response and/or catabolism. Several clinical reasons have prompted our choice of NMB for study but we are confident that lesions learned in this system will advance understanding of other microbe-host defense interactions as well, thus contributing to the control of disease and the improvement of health.